COV-AID: Treatment of COVID-19 Patients With Anti-interleukin Drugs

Sponsor

University Hospital, Ghent (Other)

Overall Status

Completed

CT.gov ID

NCT04330638

Collaborator

Belgium Health Care Knowledge Centre (Other)

342

Enrollment

Locations

Arms

12.3

Actual Duration (Months)

22.8

Patients Per Site

1.9

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study is to test the safety and effectiveness of individually or simultaneously blocking IL-6 and IL-1 versus standard of care on blood oxygenation and systemic cytokine release syndrome in patients with COVID-19 coronavirus infection and acute hypoxic respiratory failure and systemic cytokine release syndrome

Condition or Disease	Intervention/Treatment	Phase
COVID-19	Other: Usual Care Drug: Anakinra Drug: Siltuximab Drug: Tocilizumab	Phase 3

Detailed Description

There are currently no treatments directed at halting the cytokine storm and acute lung injury to stop the progression from manageable hypoxia to frank respiratory failure and ARDS in patients with COVID-19 infection. Preventing progression from early acute hypoxia and cytokine release syndrome to frank hypoxic respiratory failure and ARDS could have a huge impact on the foreseeable overflow of the ICU units. In ventilated patients, preventing the onset of ARDS, or shortening ICU stay could also be crucial in this regard.

The clinical status after 15 days treatment is evaluated to measure the effectiveness of tocilizumab, tocilizumab and anakinra, siltuximab, siltuximab and anakinra and anakinra on restoring lung homeostasis,using single IV injection (siltuximab or tocilizumab) combined or not with daily subcutaneous injections of anakinra until 28 days or hospital discharge, whichever is first. During the treatment period, daily clinical assesments of severity, daily laboratory check-up, measurements of oxygen saturation (pulse oximetry) in relation to FiO2, regular arterial blood gas measurements, regular chest X-rays, chest CT scans on indication will be performed.

Study Design

Study Type:

Interventional

Actual Enrollment :

342 participants

Allocation:

Randomized

Intervention Model:

Factorial Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Prospective, Randomized, Factorial Design, Interventional Study to Compare the Safety and Efficacy of Combinations of Blockade of Interleukin-6 Pathway and Interleukin-1 Pathway to Best Standard of Care in Improving Oxygenation and Short- and Long-term Outcome of COVID-19 Patients With Acute Hypoxic Respiratory Failure and Systemic Cytokine Release Syndrome

Actual Study Start Date :

Apr 3, 2020

Actual Primary Completion Date :

Dec 18, 2020

Actual Study Completion Date :

Apr 12, 2021

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Usual Care	Other: Usual Care Usual Care
Active Comparator: Anakinra	Drug: Anakinra Anakinra will be given as a daily subcutaneous injection of 100 mg for 28 days or until hospital discharge, whichever is first Other Names: KINERET®
Active Comparator: Siltuximab	Drug: Siltuximab Siltuximab will be given via single IV infusion at a dose of 11 mg/kg Other Names: SYLVANT®
Active Comparator: Anakinra + Siltuximab	Drug: Anakinra Anakinra will be given as a daily subcutaneous injection of 100 mg for 28 days or until hospital discharge, whichever is first Other Names: KINERET® Drug: Siltuximab Siltuximab will be given via single IV infusion at a dose of 11 mg/kg Other Names: SYLVANT®
Active Comparator: Tocilizumab	Drug: Tocilizumab Tocilizumab will be given via single IV infusion at a dose of 8 mg/kg with a maximum infusion of 800 mg/injection Other Names: ROACTEMRA®
Active Comparator: Anakinra + Tocilizumab	Drug: Anakinra Anakinra will be given as a daily subcutaneous injection of 100 mg for 28 days or until hospital discharge, whichever is first Other Names: KINERET® Drug: Tocilizumab Tocilizumab will be given via single IV infusion at a dose of 8 mg/kg with a maximum infusion of 800 mg/injection Other Names: ROACTEMRA®

Outcome Measures

Primary Outcome Measures

Time to Clinical Improvement [at day 15]
defined as the time from randomization to either an improvement of two points on a six-category ordinal scale or discharge from the hospital: Death Hospitalized, on invasive mechanical ventilation or ECMO; Hospitalized, on non-invasive ventilation or high flow oxygen devices; Hospitalized, requiring supplemental oxygen Hospitalized, not requiring supplemental oxygen Not hospitalized

Secondary Outcome Measures

Time to improvement in oxygenation [during hospital admission (up to 28 days)]
defined as independece from supplemental oxygen
Mean change in oxygenation [day 1, day 15 or hospital discharge, whichever is first]
defined by Pa02/FiO2 ratio while breading room air
Number of days with hypoxia [during hospital admission (up to 28 days)]
Number of days of supplemental oxygen use [during hospital admission (up to 28 days)]
Time to absence fever for more than 48h without antipyretics [during hospital admission (up to 28 days)]
Number of days with fever [during hospital admission (up to 28 days)]
Time to halving of CRP levels compared to peak value during trial [during hospital admission (up to 28 days)]
Time to halving of ferritin levels compared to peak value during trial [during hospital admission (up to 28 days)]
Incidence of AEs (Adverse Events) [during hospital admission (up to 28 days)]
Incidence of SAEs (Serious Adverse Events) [during hospital admission (up to 28 days)]
Duration of hospital stay [during hospital admission (up to 28 days)]
Duration of hospital stay in survivors [during hospital admission (up to 28 days)]
Mean change of SOFA score (Sequential Organ Failure Assessment) between day 1 and day 7 [Day 1, day 7or hospital discharge, whichever is first]
SOFA score: 0 (best) - 24 (worse)
Mean change of SOFA score between day 1 and day 15 [day 1, day 15 or hospital discharge, whichever is first]
SOFA score: 0 (best) - 24 (worse)
Percentage of patients reporting each severity rating on a 6-point ordinal scale in relation to serum IL-1 [at day 15 or hospital discharge, whichever is first]
6-point ordinal scale: Death Hospitalized, on invasive mechanical ventilation or ECMO; Hospitalized, on non-invasive ventilation or high flow oxygen devices; Hospitalized, requiring supplemental oxygen Hospitalized, not requiring supplemental oxygen Not hospitalized
Percentage of patients reporting each severity rating on a 6-point ordinal scale in relation to serum IL-6 [at day 15 or hospital discharge, whichever is first]
6-point ordinal scale: Death Hospitalized, on invasive mechanical ventilation or ECMO; Hospitalized, on non-invasive ventilation or high flow oxygen devices; Hospitalized, requiring supplemental oxygen Hospitalized, not requiring supplemental oxygen Not hospitalized
Incidence of nosocomial bacterial or invasive fungal infection [during hospital admission (up to 28 days)]
incidence of secondary haemophagocytic lymphohistiocytosis [during hospital admission (up to 28 days)]
defined by Hs (Hemophagocytic Syndrome) score
Incidence of secondary haemophagocytic lymphohistiocytosisscore in relation to serum IL-1 [during hospital admission (up to 28 days)]
defined by Hs score
Incidence of secondary haemophagocytic lymphohistiocytosis in relation to serum IL-6 [during hospital admission (up to 28 days)]
defined by Hs score
Time to first use of high-flow oxygen devices, non-invasive or invasive mechanical ventilation in non-ventilated patients [during hospital admission (up to 28 days)]
Time to first use of salvage systemic steroids in ventilated patients [during hospital admission (up to 28 days)]
Number of ventilator free days [during hospital admission (up to 28 days)]
Duration of mechanical ventilation in ventilated patients [during hospital admission (up to 28 days)]
Duration of ICU stay in patients that enrolled in trial while already on invasive or non-invasive mechanical ventilation [during hospital admission (up to 28 days)]
Time to progression to ARDS in ventilated patients, according to the adapted Berlin criteria [during hospital admission (up to 28 days)]
Time to progression to ARDS in ventilated patients according to IL-1 [during hospital admission (up to 28 days)]
Time to progression to ARDS in ventilated patients according to IL-6 [during hospital admission (up to 28 days)]
All-cause mortality rate (excluding group that entered during ventilation) [during hospital admission (up to 28 days)]
Percentage of patients in clinical status on 6-point Ordinal Scale [at 10-20 weeks follow-up]
Incidence of lung function abnormalities [at 10-20 weeks follow-up]
Incidence of lung fibrosis on chest CT scan [at 10-20 weeks follow-up]
All-cause mortality rate [at 10-20 weeks follow-up]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Recent ( ≥ 6 days of flu-like symptoms or malaise yet ≤16 days of flu-like symptoms or malaise prior to randomization) infection with COVID-19.
Confident COVID-19 diagnosis confirmed by antigen detection test and/or PCR and/or positive serology, or any emerging and validated diagnostic laboratory test for COVID-19 within this period.
In some patients, it may be impossible to get a confident laboratory confirmation of COVID-19 diagnosis after 24h of hospital admission because viral load is low and/or problems with diagnostic sensitivity. In those cases, in absence of an alternative diagnosis, and with highly suspect bilateral ground glass opacities on recent (<24h) chest-CT scan (confirmed by a radiologist and pulmonary physician as probable COVID-19), and a typical clinical and chemical diagnosis with signs of cytokine release syndrome, a patient can be enrolled as probable COVID-19 infected. In all cases, this needs confirmation by later seroconversion.
Presence of hypoxia defined as PaO2/FiO2 below 350 while breathing room air in upright position or PaO2/FiO2 below 280 on supplemental oxygen and immediately requiring high flow oxygen device or mechanical ventilation
signs of cytokine release syndrome defined as ANY of the following:

serum ferritin concentration >1000 mcg/L and rising since last 24h
single ferritin above 2000 mcg/L in patients requiring immediate high flow oxygen device or mechanical ventilation
lymphopenia defined as <800 lymphocytes/microliter) and two of the following extra criteria

Ferritin > 700 mcg/L and rising since last 24h
increased LDH (above 300 IU/L) and rising last 24h
D-Dimers > 1000 ng/mL and rising since last 24h
CRP above 70mg/L and rising since last 24h and absence of bacterial infection
if three of the above are present at admission, no need to document 24h rise
Chest X-ray or CT scan showing bilateral infiltrates within last 2 days
Admitted to specialized COVID-19 ward or an ICU ward taking care of COVID-19 patients
Age ≥ 18yrs
Male or Female
Willing and able to provide informed consent or legal representative willing to provide informed consent

Exclusion Criteria:

Patients with known history of serious allergic reactions, including anaphylaxis, to any of the study medications, or any component of the product.
mechanical ventilation > 24 h at Randomization
Patient on ECMO at time of screening
clinical frailty scale above 3 (This frailty score is the patient status before first symptoms of COVID-19 episode.)
active bacterial or fungal infection
unlikely to survive beyond 48h
neutrophil count below 1500 cells/microliter
platelets below 50.000/microliter
Patients enrolled in another investigational drug study
patients on high dose systemic steroids (> 20 mg methylprednisolone or equivalent) for COVID-19 unrelated disorder
patients on immunosuppressant or immunomodulatory drugs
patients on current anti-IL1 or anti-IL6 treatment
signs of active tuberculosis
serum transaminase levels >5 times upper limit of normal
bowel perforation or diverticulitis
pregnant or breastfeeding females (all female subjects deemed of childbearing potential by the investigator must have negative pregnancy test at screening)
Women of childbearing potential must have a negative serum pregnancy test pre-dose on day 1. Woùmen of childbearing potential must consistently and correctly use (during the entire treatment period and 3 months after last reatment) 1 highly effective method for contraception.

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	AZ Sint-Jan Brugge	Brugge	Belgium	8000
2	University Hospital Saint-Pierre	Brussels	Belgium	1000
3	Erasmus University Hospital	Brussels	Belgium	1070
4	University Hospital Saint-Luc	Brussels	Belgium	1200
5	University Hospital Antwerp	Edegem	Belgium	2650
6	Ziekenhuis Oost-Limurg	Genk	Belgium	3600
7	AZ Sint-Lucas	Gent	Belgium	9000
8	University Hospital Ghent	Gent	Belgium	9000
9	Jessa ZH	Hasselt	Belgium	3500
10	University Hospital Brussels	Jette	Belgium	1090
11	CHU Tivoli	La Louvière	Belgium	7100
12	CHR de la Citadelle	Liège	Belgium	4000
13	University Hospital Liège	Liège	Belgium	4000
14	Cliniques Saint-Pierre Ottignies	Ottignies-Louvain-la-Neuve	Belgium	1340
15	AZ Delta	Roeselare	Belgium	8800